Enhanced Tumor Metastasis Research Articles

NAMPT enhances LOX expression and promotes metastasis in human chondrosarcoma cells by inhibiting miR-26b-5p synthesis.

Chondrosarcoma is a malignant bone tumor that emerges from abnormalities in cartilaginous tissue and is related with lung metastases. Nicotinamide phosphoribosyltransferase (NAMPT) is an adipocytokine reported to enhance tumor metastasis. Our results from clinical samples and the Gene Expression Omnibus data set reveal that NAMPT levels are markedly higher in chondrosarcoma patients than in normal individuals. NAMPT stimulation significantly increased lysyl oxidase (LOX) production in chondrosarcoma cells. Additionally, NAMPT increased LOX-dependent cell migration and invasion in chondrosarcoma by suppressing miR-26b-5p generation through the c-Src and Akt signaling pathways. Overexpression of NAMPT promoted chondrosarcoma metastasis to the lung in vivo. Furthermore, knockdown of LOX counteracted NAMPT-facilitated metastasis. Thus, the NAMPT/LOX axis presents a novel target for treating the metastasis of chondrosarcoma.

Visfatin Facilitates VEGF-D-Induced Lymphangiogenesis through Activating HIF-1α and Suppressing miR-2277-3p in Human Chondrosarcoma.

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Lymphangiogenesis plays an essential role in cancer metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with VEGF-D generation and lymphangiogenesis in chondrosarcoma remains undetermined. Our results from clinical samples reveal that VEGF-D levels are markedly higher in chondrosarcoma patients than in normal individuals. Visfatin stimulation promotes VEGF-D-dependent lymphatic endothelial cell lymphangiogenesis. We also found that visfatin induces VEGF-D production by activating HIF-1α and reducing miR-2277-3p generation through the Raf/MEK/ERK signaling cascade. Importantly, visfatin controls chondrosarcoma-related lymphangiogenesis in vivo. Therefore, visfatin is a promising target in the treatment of chondrosarcoma lymphangiogenesis.

GSK3β and UCHL3 govern RIPK4 homeostasis via deubiquitination to enhance tumor metastasis in ovarian cancer.

Receptor-interacting protein kinase 4 (RIPK4) is increasingly recognized as a pivotal player in ovarian cancer, promoting tumorigenesis and disease progression. Despite its significance, the posttranslational modifications dictating RIPK4 stability in ovarian cancer remain largely uncharted. In this study, we first established that RIPK4 levels are markedly higher in metastatic than in primary ovarian cancer tissues through single-cell sequencing. Subsequently, we identified UCHL3 as a key deubiquitinase that regulates RIPK4. We elucidate the mechanism that UCHL3 interacts with and deubiquitinates RIPK4 at the K469 site, removing the K48-linked ubiquitin chain and thus enhancing RIPK4 stabilization. Intriguingly, inhibition of UCHL3 activity using TCID leads to increased RIPK4 ubiquitination and degradation. Furthermore, we discovered that GSK3β-mediated phosphorylation of RIPK4 at Ser420 enhances its interaction with UCHL3, facilitating further deubiquitination and stabilization. Functionally, RIPK4 was found to drive the proliferation and metastasis of ovarian cancer in a UCHL3-dependent manner both in vitro and in vivo. Importantly, positive correlations between RIPK4 and UCHL3 protein expression levels were observed, with both serving as indicators of poor prognosis in ovarian cancer patients. Overall, this study uncovers a novel pathway wherein GSK3β-induced phosphorylation of RIPK4 strengthens its interaction with UCHL3, leading to increased deubiquitination and stabilization of RIPK4, thereby promoting ovarian cancer metastasis. These findings offer new insights into the molecular underpinnings of ovarian cancer and highlight potential therapeutic targets for enhancing antitumor efficacy.

The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Extracellular vesicles called exosomes are primarily used as mediators of intercellular signal transmission to control tumor metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with exosome generation in chondrosarcoma motility remains undetermined. Our results found that overexpressing visfatin augments the production of exosomes from chondrosarcoma cells. Visfatin-treated chondrosarcoma exosomes educate macrophage polarization towards the M2 but not M1 phenotype. Interestingly, M2 macrophages polarized by exosomes return to chondrosarcoma cells to facilitate cell motility. According to these findings, chondrosarcoma cells emit more exosomes when treated with visfatin. The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.

Tiam1 methylation by NSD2 promotes Rac1 signaling activation and colon cancer metastasis.

Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.

Fiber Microarchitecture in Interpenetrating Collagen-Alginate Hydrogel with Tunable Mechanical Plasticity Regulates Tumor Cell Migration.

The fiber structures of tumor microenvironment (TME) are well-known in regulating tumor cell behaviors, and the plastic remolding of TME has recently been suggested to enhance tumor metastasis as well. However, the interrelationship between the fiber microarchitecture and matrix plasticity is inextricable by existing in vitro models. The individual roles of fiber microarchitecture and matrix plasticity in tuning tumor cell behaviors remain elusive. This study develops an interpenetrating collagen-alginate hydrogel platform with independently tunable matrix plasticity and fiber microarchitecture through an interpenetrating strategy of alginate networks and collagen I networks. With this hydrogel platform, it is demonstrated that tumor cells in high plasticity hydrogels are more extensive and aggressive than in low plasticity hydrogels and fiber structures only have influence in high plasticity hydrogels. The study further elucidates the underlying mechanisms through analyzing the distribution of forces within the matrix and tracking the focal adhesions (FAs) and finds that highly plastic hydrogels can activate the FAs formation, whereas the maturation and stability of FAs are dominated by fiber dispersion. This study not only establishes new ideas on how cells interact with TME cues but also would help to further finely tailor engineered hydrogel platforms for studying tumor behaviors in vitro.

LncRNA MIR4435-2HG drives cancer progression by modulating cell cycle regulators and mTOR signaling in stroma-enriched subtypes of urothelial carcinoma of the bladder

BackgroundThe risk for recurrence and metastasis after treatment for urothelial carcinoma of the bladder (UCB) is high. Therefore, identifying efficient prognostic markers and novel therapeutic targets is urgently needed. Several long noncoding RNAs (lncRNAs) have been reported to be correlated with UCB progression. In this study, we found that the subtype-specific lncRNA MIR4435-2 host gene (MIR4435-2HG) plays a novel oncogenic role in UCB.MethodsRNA-Seq data of TCGA/BLCA were analyzed. The expression of MIR4435-2HG was measured by qRT-PCR in 16 pairs of bladder cancer tissues and adjacent normal tissues. The clinical relecance of MIR4435-2HG was validated via in situ hybridization performed on an in-house cohort of 116 UCB patient samples. RNA pull-down followed by mass spectrometry was performed to identify MIR4435-2HG-binding proteins. To identify signaling pathways involved in MIR4435-2HG activity, comprehensive in vitro and in vivo studies and RNA-Seq assays were performed using UCB cells in which MIR4435-2HG expression was knocked down or exogenously overexpressed. In addition, we performed RNA immunoprecipitation and Western blot analyses to validate the identified MIR4435-2HG-binding proteins and to determine the molecular mechanisms by which MIR4435-2HG promotes UCB progression.ResultsWe found that MIR4435-2HG was significantly upregulated in the stromal-enriched subtype of UCB. Increased MIR4435-2HG expression was positively correlated with a high histological grade, advanced T stages, larger tumors, lymph node metastasis and a poor prognosis. In vitro experiments revealed that MIR4435-2HG expression silencing suppressed cell proliferation and induced apoptosis. Inhibition of MIR4434-2HG delayed xenograft tumor growth, while MIR4435-2HG overexpression reversed the MIR4435-2HG silencing-induced inhibition of UCB tumor phenotype acquisition. Mechanistically, we found that MIR4435-2HG positively regulated the expression of a variety of cell cycle regulators, including BRCA2 and CCND1. Knocking down MIR4435-2HG increased the sensitivity of tumor cells to the VEGFR inhibitor cediranib. Furthermore, we found that MIR4435-2HG regulated mTOR signaling and epithelial-mesenchymal transition (EMT) signaling pathways by modulating the phosphorylation of mTOR, 70S6K and 4EBP1. Finally, we confirmed that MIR4435-2HG enhances tumor metastasis through regulation of the EMT pathway.ConclusionsOur data indicate that upregulated MIR4435-2HG expression levels are significantly correlated with a poor prognosis of UCB patients. MIR4435-2HG promotes bladder cancer progression, mediates cell cycle (de)regulation and modulates mTOR signaling. MIR4435-2HG is an oncogenic lncRNA in UCB that may serve as a diagnostic and therapeutic target.

Lactate in the tumor microenvironment: A rising star for targeted tumor therapy.

Metabolic reprogramming is one of fourteen hallmarks of tumor cells, among which aerobic glycolysis, often known as the "Warburg effect," is essential to the fast proliferation and aggressive metastasis of tumor cells. Lactate, on the other hand, as a ubiquitous molecule in the tumor microenvironment (TME), is generated primarily by tumor cells undergoing glycolysis. To prevent intracellular acidification, malignant cells often remove lactate along with H+, yet the acidification of TME is inevitable. Not only does the highly concentrated lactate within the TME serve as a substrate to supply energy to the malignant cells, but it also works as a signal to activate multiple pathways that enhance tumor metastasis and invasion, intratumoral angiogenesis, as well as immune escape. In this review, we aim to discuss the latest findings on lactate metabolism in tumor cells, particularly the capacity of extracellular lactate to influence cells in the tumor microenvironment. In addition, we examine current treatment techniques employing existing medications that target and interfere with lactate generation and transport in cancer therapy. New research shows that targeting lactate metabolism, lactate-regulated cells, and lactate action pathways are viable cancer therapy strategies.

Acute respiratory distress syndrome enhances tumor metastasis into lungs: Role of BRD4 in the tumor microenvironment.

Acute respiratory distress syndrome (ARDS) is associated with severe lung inflammation, edema, hypoxia, and high vascular permeability. The COVID-19-associated pandemic ARDS caused by SARS-CoV-2 has created dire global conditions and has been highly contagious. Chronic inflammatory disease enhances cancer cell proliferation, progression, and invasion. We investigated how acute lung inflammation activates the tumor microenvironment and enhances lung metastasis in LPS induced in vitro and in vivo models. Respiratory illness is mainly caused by cytokine storm, which further influences oxidative and nitrosative stress. The LPS-induced inflammatory cytokines made the conditions suitable for the tumor microenvironment in the lungs. In the present study, we observed that LPS induced the cytokine storm and promoted lung inflammation via BRD4, which further caused the nuclear translocation of p65 NF-κB and STAT3. The transcriptional activation additionally triggers the tumor microenvironment and lung metastasis. Thus, BRD4-regulated p65 and STAT3 transcriptional activity in ARDS enhances lung tumor metastasis. Moreover, LPS-induced ARDS might promote the tumor microenvironment and increase cancer metastasis into the lungs. Collectively, BRD4 plays a vital role in inflammation-mediated tumor metastasis and is found to be a diagnostic and molecular target in inflammation-associated cancers.

WWP2 overexpression inhibits the antitumor effects of doxorubicin in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common liver cancer that accounts for 90% of cases. Doxorubicin exhibits a broad spectrum of antitumor activity and is one of the most active agents in HCC. WW domain-containing protein 2 (WWP2) is highly expressed in HCC tissues and activates protein kinase B (AKT) signaling pathway to enhance tumor metastasis. However, the role of WWP2 in the glycolysis and antitumor effects of doxorubicin and the epigenetic alterations of WWP2 in HCC remain to be elucidated. The levels of WWP2 and N6-methyladenosine methyltransferase-like 3 (METTL3) in clinical samples and cells were investigated. WWP2 were silenced or overexpressed to study the role of WWP2 in regulating cell proliferation, colony formation, and glycolysis. RNA immunoprecipitation was performed to test m6 A levels. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot were used to measure mRNA and protein, respectively. WWP2 silencing inhibits cell proliferation, colony formation, and glycolysis, while WWP2 overexpression has the inverse effects via the AKT signaling pathway. Silencing WWP2 enhances doxorubicin's antitumor effect, while WWP2 overexpression suppresses doxorubicin's antitumor effect. Data also support that METTL3 mediates WWP2 m6A modification, and m6A reader, IGF2BP2, binds to the methylated WWP2 to promote the stability of WWP2, leading to upregulation of WWP2. METTL3 mediates WWP2 m6A modification, which can be recognized and bound by IGF2BP2 to increase the stability of WWP2, leading to WWP2 overexpression which inhibits the antitumor effects of doxorubicin through METTL3/WWP2/AKT/glycolysis axis.

Loss of EMP1 promotes the metastasis of human bladder cancer cells by promoting migration and conferring resistance to ferroptosis through activation of PPAR gamma signaling

Metastasis, in which cancer cells detach from the original site and colonise other organs, is the primary cause of death induced by bladder cancer (BCa). Epithelial Membrane Protein 1 (EMP1) is dysregulated in many human cancers, and its clinical significance and biological function in diseases, including BCa, are largely unclear. Here, we demonstrated that EMP1 was downregulated in BCa cells. The deficiency of EMP1 promotes migration and confers resistance to ferroptosis/oxidative stress in BCa cells, favouring tumour cell metastasis. Mechanistically, we demonstrated that EMP1 deficiency enhanced tumour metastasis by increasing PPARG expression and promoting its activation, leading to upregulation of pFAK(Y397) and SLC7A11, which promoted cell migration and anti-ferroptotic cell death respectively. Moreover, we found EMP1-deficient sensitized cells to PPARG's ligand, which effect are metastatic phenotype promoted and could be mitigated by FABP4 knockdown. In conclusion, our study, for the first time, reveals that EMP1 deficiency promotes BCa cell migration and confers resistance to ferroptosis/oxidative stress, thus promoting metastasis of BCa via PPARG. These results revealed a novel role of EMP1-mediated PPARG in bladder cancer metastasis.

MicroRNA-15b-5p encapsulated by M2 macrophage-derived extracellular vesicles promotes gastric cancer metastasis by targeting BRMS1 and suppressing DAPK1 transcription

BackgroundExtracellular vesicles (EVs) derived from tumor-associated macrophages are implicated in the progression and metastasis of gastric cancer (GC) via the transfer of molecular cargo RNAs. We aimed to decipher the impact of microRNA (miR)-15b-5p transferred by M2 macrophage-derived EVs in the metastasis of GC.MethodsExpression of miR-15b-5p was assessed and the downstream genes of miR-15b-5p were analyzed. GC cells were subjected to gain- and loss-of function experiments for miR-15b-5p, BRMS1, and DAPK1. M2 macrophage-derived EVs were extracted, identified, and subjected to co-culture with GC cells and their biological behaviors were analyzed. A lung metastasis model in nude mice was established to determine the effects of miR-15b-5p on tumor metastasis in vivo.ResultsmiR-15b-5p was upregulated in GC tissues and cells as well as in M2 macrophage-derived EVs. miR-15b-5p promoted the proliferative and invasive potentials, and epithelial-mesenchymal transition (EMT) of GC cells. M2 macrophage-derived EVs could transfer miR-15b-5p into GC cells where it targeted BRMS1 by binding to its 3’UTR. BRMS1 was enriched in the DAPK1 promoter region and promoted its transcription, thereby arresting the proliferative and invasive potentials, and EMT of GC cells. In vivo experiments demonstrated that orthotopic implantation of miR-15b-5p overexpressing GC cells in nude mice displayed led to enhanced tumor metastasis by inhibiting the BRMS1/DAPK1 axis.ConclusionsOverall, miR-15b-5p delivered by M2 macrophage-derived EVs constitutes a molecular mechanism implicated in the metastasis of GC, and may thus be considered as a novel therapeutic target for its treatment.

MetaLnc9-Antisense RNA Contributes to Lung Cancer Metastasis via Modulating RNA-RNA Duplex with MetaLnc9.

Lung cancer is a common life-threatening tumor with high malignancy and high invasiveness. Long non-coding RNAs (lncRNAs) are involved in almost every stage of tumor initiation and progression. Here, we identified an antisense lncRNA, MetaLnc9 antisense (Metalnc9-AS), which arises from the antisense strand of Metalnc9, located on chr9q34.11, while its biological function and mechanism are not clear in lung cancer. In this study, we demonstrated that the expression of Metalnc9-AS was upregulated in non-small cell lung cancer (NSCLC) tissues compared with corresponding non-tumorous tissues. The gain of MetaLnc9-AS was highly associated with the malignant features of NSCLC. Overexpression of MetaLnc9-AS enhanced tumor metastasis in vitro and in vivo. Mechanically, MetaLnc9-AS could form an RNA-RNA hybrid with its cognate sense counterpart, MetaLnc9, to regulate its expression in NSCLC cells, and that such complexes were protected from ribonuclease degradation. Thus, Metalnc9-AS might be a potential and effective treatment for NSCLC.

Fibronectin enhances tumor metastasis through B7-H3 in clear cell renal cell carcinoma.

B7 homolog 3 (B7‐H3) plays an important role in tumor biology, but the molecular mechanism underlying the role of B7‐H3 in tumor metastasis remains unclear. In this article, our analysis of The Cancer Genome Atlas database suggested that B7‐H3 expression is associated with poor prognosis of patients with clear cell renal cell carcinoma (ccRCC). B7‐H3 knockdown affected the expression of metastasis‐related genes and significantly suppressed the metastasis of ccRCC cells, but it had no significant effect on the proliferation of ccRCC cells. Database analysis revealed a strong positive correlation between B7‐H3 and fibronectin (FN) in ccRCC cells, and further study also confirmed that FN interacts with B7‐H3. Silencing FN expression inhibited the migration and invasion of ccRCC cells, whereas exogenous FN promoted the migration and invasion of ccRCC cells, which was accompanied by activation of kinases [namely, phosphorylated (p)‐phosphoinositide 3‐kinase, p‐protein kinase B, p‐p38 and p‐extracellular regulated protein kinase]. B7‐H3 knockdown abolished the prometastatic effect of FN. In conclusion, our data suggest that B7‐H3 binds to exogenous FN and promotes the metastasis of ccRCC cells.

Crosslink between p53 and metastasis: focus on epithelial-mesenchymal transition, cancer stem cell, angiogenesis, autophagy, and anoikis.

P53, as a tumor suppressor gene, is believed to be one of the most mutated genes in cancer cells. The mutant forms of this protein often play a tumorigenic role in cancer cells. Recent evidence shows that p53 plays a critical role in the migration, metastasis, and invasion of cancer cells. The present article aims to investigate the molecular mechanism that induces metastasis in cancer cells generated by the mutant P53, and to highlight the compounds targeting mutant-p53 together with their clinical applications. A detailed literature search was conducted to find information about the role of the mutant-p53 in the processes involved in metastasis in various databases. A growing body of evidence suggests that Mutant-p53 enhances tumor metastasis affecting the Epithelial-mesenchymal transition (EMT) process, cancer stem cells, angiogenesis, autophagy, anoikis, and any other mechanisms regarding metastasis. Taken together, targeting mutant-p53 by altering the processes involved in metastasis could be a potential therapeutic strategy in the treatment of metastatic cancer.

MAGE-C3 promotes cancer metastasis by inducing epithelial-mesenchymal transition and immunosuppression in esophageal squamous cell carcinoma.

BackgroundEvading immune surveillance is necessary for tumor metastasis. Thus, there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion. In this study, we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma (ESCC).MethodsThe expression of melanoma‐associated antigen C3 (MAGE‐C3) was detected using immunohistochemistry. Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma (ESCC) cells. Metastasis assays in mice were used to evaluate metastatic ability in vivo. Lymphocyte‐mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells. RNA sequencing was performed to identify differentially expressed genes between MAGE‐C3 overexpressing ESCC cells and control cells. Gene ontology (GO) enrichment analyses was performed to identify the most altered pathways influenced by MAGE‐C3. The activation of the interferon‐γ (IFN‐γ) pathway was analyzed using Western blotting, GAS luciferase reporter assays, immunofluorescence, and flow cytometry. The role of MAGE‐C3 in the IFN‐γ pathway was determined by Western blotting and immunoprecipitation. Furthermore, immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases.ResultsMAGE‐C3 was overexpressed in ESCC tissues. High expression of MAGE‐C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC. Functional experiments revealed that MAGE‐C3 promoted tumor metastasis by activating the epithelial‐mesenchymal transition (EMT). MAGE‐C3 repressed antitumor immunity and regulated cytokine secretion of T cells, implying an immunosuppressive function. Mechanistically, MAGE‐C3 facilitated IFN‐γ signaling and upregulated programmed cell death ligand 1 (PD­L1) by binding with IFN‐γ receptor 1 (IFNGR1) and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1 (STAT1). Interestingly, MAGE‐C3 displayed higher tumorigenesis in immune‐competent mice than in immune‐deficient nude mice, confirming the immunosuppressive role of MAGE‐C3. Furthermore, mice bearing MAGE‐C3‐overexpressing tumors showed worse survival and more lung metastases with decreased CD8+ infiltrated T cells and increased programmed cell death 1 (PD‐1)+CD8+ infiltrated T cells.ConclusionMAGE‐C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance, and could be a potential prognostic marker and therapeutic target.

Candidate oncogene circularNOP10 mediates gastric cancer progression by regulating miR-204/SIRT1 pathway

The role of circular RNA (circRNA) in gastric cancer (GC) is attracting increasing attention. CircNOP10 (hsa_circ-0034351) has been reported to be upregulated in human GC tissue. However, the biological role and mechanism of circNOP10 in GC remain unknown. Circular RNA expression profile of GC was detected based on microarray, and circNOP10 was identified for the subsequent investigation. Clinical samples of GC tissue and patient blood were obtained from the Zhongda Hospital, Southeast University. The different degraded GC cell lines were presented in our laboratory. The function and mechanism of circNOP10 in GC were investigated using Western blot, qRT-PCR, flow cytometry, in situ hybridization and pull down experiment. The results indicated that increased circNOP10 in GC tissue was involved in tumor stage and prognosis. In addition, circNOP10 sponged microRNA-24 (miR-204)-mediated biological processes through sirtuin 1 (SIRT1), which further confirmed that the circNOP10/miR-204/SIRT1 pathway promoted proliferation and migration as well as epithelial-mesenchymal transition (EMT) through the NF-κβ pathway in GC cell lines. Candidate oncogene circNOP10 mediated GC cell proliferation, arrest cell cycle in G2/M phase, induced cell apoptosis, enhanced tumor metastasis, as well as EMT by activating the miR-204/SIRT1 pathway, suggesting that it may serve as a potential biomarker in GC therapy.

Osteosarcoma-Derived Small Extracellular Vesicles Enhance Tumor Metastasis and Suppress Osteoclastogenesis by miR-146a-5p.

Osteosarcoma is the most frequent type of primary bone tumor in children and adolescents, thus care for patients with malignant osteosarcoma is strongly required. The roles of small extracellular vesicles (SEVs) in enhancing metastases have been demonstrated in multiple tumors, but they are still poorly understood in osteosarcoma. Hence, this study investigated the effects of SEVs on progression and the tumor microenvironment in mice and patients. In an orthotopic implantation study, we found that osteosarcoma-derived SEVs had the potential to enhance metastases and angiogenesis. In addition, osteosarcoma-derived SEVs decreased the number of mature osteoclasts in vivo. In vitro osteoclastogenesis studies revealed that the inhibition of osteoclast maturation by osteosarcoma-derived SEVs was mediated by suppressing the NF-κB signal pathway. MicroRNA analysis of SEVs from different malignant human osteosarcomas revealed that miR-146a-5p was involved in the inhibition of osteoclastogenesis. In osteosarcoma patients, lower numbers of osteoclasts in biopsy specimens at the first visits were correlated with higher malignancy. These findings indicated that osteosarcoma-derived SEVs enhance distant metastasis of osteosarcomas by inhibiting osteoclast maturation, which may be a useful prognostic marker. This diagnostic method may enable to predict malignancy at early stage, and help to provide optimal care to patients with risk of high malignancy.

Prognostic significance of transforming growth factor β receptor II in clinical stage III breast cancer patients - a pilot study.

Transforming growth factor-β (TGFβ) has a dual function in breast cancer, having a tumor suppressor activity in early carcinomas while enhancing tumor metastasis in advanced breast carcinoma. Consequently, the prognostic role of TGFβ and its signaling cascade in breast cancer remain unclear. To investigate the relationship between TβRII expression, clinic-pathological characteristics, and prognostic significance of TβRII expression in clinical stage III breast cancer. Biopsy from the primary tumor was obtained from 30 newly diagnosed clinical stage III breast cancer patients before receiving any therapy. Expression of TβRII, ER, PR, Her2 and Ki-67 was assessed by immunohistochemistry. TβRII expression was positive in 66.7% of cases and was significantly associated with advanced nodal stage and distant metastases. After a median follow up of 42.3 months, TβRII was associated with poor disease-free survival and it was an independent factor for predicting the poor outcome for breast cancer patients, especially in node positive tumors, ER/PR positive and Her2-negative tumors. These findings suggest the usage of therapeutic drugs that target TGFβ in advanced breast cancer patients may be effective. Nevertheless, blockage of the tumor promoting and sparing of the tumor suppressor effect of TGFβ pathway should be taken into consideration. We suggest that these therapies might have more benefit in ER and PR positive tumors.

The effect of Ananixanthone in TGF‐ ß1 signaling

Transforming growth factor beta 1(TGF‐ß1) is a famous known growth factor which promotes malignancy and enhances tumor metastasis by inducing epithelial‐mesenchymal transition (EMT). Ananixanthone(GMP15), a derivative of xanthone, is extracted from Calophyllum teysmannii and has been reported to show lower toxicity compared to xanthone. Previous study has showed that xanthone repressed TGF‐ ß1‐mediated EMT, however there is no study about GMP15. Hence, in this study, we determine to study the effect of GMP15 in TGF‐ ß1 signaling. We found that GMP15 suppressed TGF‐β1‐induced PAI‐1 reporter gene activation and Smad2/3 phosphorylation in various type of cell. Also, GMP15 repressed TGF‐ ß1‐mediated expression of N‐cadherin and Fibronectin as well as abolished repression of E‐cadherin in HepG2 cell, thus blocking TGF‐ ß1‐mediated EMT. Our preliminary finding showed that GMP15 might be a potential inhibitor of TGF‐ ß1 signaling. Finding the underlying mechanism of GMP15 in TGF‐ ß1 signaling might help provide a new choice of cancer treatment.